Clinical spectrum of SCN1A mutations
Clinical spectrum of SCN1A mutations
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DOI：
10.1111/j.1528-1167.2009.02115.x
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发表时间：
2009-01-01
期刊：
影响因子：
5.6
通讯作者：
Marini, Carla
中科院分区：
文献类型：
--
作者：
Gambardella, Antonio;Marini, Carla
NaV1.1 神经元钠通道 α 亚基 (SCN1A) 基因突变已在一系列癫痫综合征中得到记录，从相对良性的全身性癫痫伴热性惊厥附加 (GEFS(+)) 到严重的婴儿期肌阵挛性癫痫 (SMEI)，以及罕见的家族性偏头痛病例。迄今为止，已鉴定出 300 多种新突变，其中错义突变在 GEFS(+) 中最常见，而更有害的突变（无义突变、移码突变）代表了大多数 SMEI 突变。 SMEI 患者还发现微小染色体异常，包括 SCN1A 缺失、扩增和重复。缺失的大小范围从单个外显子到超出 SCN1A 并涉及连续基因的异常。 SMEI 中的大多数 SCN1A 突变是从头产生的。 SCN1A 突变遍布整个蛋白质结构，并且在 C 末端以及蛋白质前三个结构域的第 5 段和第 6 段之间的环中观察到一些突变聚集。迄今为止的功能研究表明通道特性的变化与临床表型之间没有一致的关系。
Mutations in the NaV1.1 neuronal sodium channel alpha-subunit (SCN1A) gene have been documented in a spectrum of epilepsy syndromes, ranging from the relatively benign generalized epilepsy with febrile seizures plus (GEFS(+)) to severe myoclonic epilepsy in infancy (SMEI), and rare cases of familial migraine. More than 300 new mutations have been identified to date, with missense mutations being the most common in GEFS(+) and more deleterious mutations (nonsense, frameshift) representing the majority of SMEI mutations. Microchromosomal abnormalities including SCN1A deletions, amplifications, and duplications are also found in patients with SMEI. Deletions range in size from one single exon to abnormalities extending beyond SCN1A and involving contiguous genes. The majority of SCN1A mutations in SMEI arise de novo. SCN1A mutations are found throughout the protein structure, and some clustering of mutations is observed in the C-terminus and the loops between segments 5 and 6 of the first three domains of the protein. Functional studies so far show no consistent relationship between changes to channel properties and clinical phenotype.